Biologics for pediatric atopic dermatitis: A protocol of a systematic review and meta-analysis

Background Atopic dermatitis is a chronic pruritic inflammatory skin disease commonly occurring in children. The objective of this study is to evaluate the treatment of pediatric atopic dermatitis with biologics, as they have displayed immense promising results in several recent clinical trials on atopic dermatitis (AD). Methods We will conduct an extensive search for RCTs in several databases, including Embase, Cochrane Library, Web of Science, and PubMed, from the inception of the study till 15th May 2022. The primary outcomes will be the proportion of patients with EASI 75/90/100 after 12–16 weeks of treatment. The secondary outcomes will include the Numerical Rating Scale (NRS), Investigator Global Assessment (IGA)0–1, body surface area (BSA), Dermatology Life Quality Index (DLQI) scores, and incidence of adverse reactions. All studies will be screened by two independent researchers. They will assess the risk of bias in the included studies according to the RCTs bias risk evaluation tool in Cochrane System Review Manual 5.1.0. Meta-analysis will be performed using RevMan V.5.3.0 software. Results The research results will provide a reference for the clinical application of biological agents in pediatric atopic dermatitis. Conclusion We aim to evaluate the efficacy and safety of biologics in pediatric atopic dermatitis cases and provide evidence-based data for easy clinical application. PROSPERO registration number CRD42022319052 (https://www.crd.york.ac.uk/PROSPERO/#joinuppage).


Introduction
Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease, with an increasing prevalence globally in all ages; it affects 13% of children and 10% of adults in the United States [1,2]. This global survey in 18 countries revealed that the prevalence of definite diagnosis of AD in children ranges from 2.7% to 20.1% [2]. Chronic itchy skin caused by AD can have a serious impact on a patient's quality of life [3,4]. Although AD can be adequately managed with topical therapies and gentle skin care practices [5], for severe cases, phototherapy, biological agents, and systemic immunosuppressants can be used in conjunction with traditional interventions [6,7]. In recent years, several studies on the pathogenesis of AD have found that the activation of T helper type 2 (Th2) inflammation-related pathways and its driving factors: interleukin (IL)-4, IL-13, and IL-31, as well as the sequential increase in the inflammatory dendritic epidermal cells, lead to altered cellular responses; thus, predisposing the patient to AD. Such extensive research has led to the development of biologics for treating AD [8,9]. Dupilumab, as a fully human IL-4Rα monoclonal antibody, can inhibit Th2-mediated inflammatory response by targeting IL-4 and IL-13 that induce inflammatory reactions [10,11]. Tralokinumab and lebrikizumab are humanized immunoglobulin (IgG4) monoclonal antibodies that inhibit the signaling pathway mediated by IL-13Rα1/IL-4Rα complex through binding to the IL-13α receptor [12]. Omalizumab is a monoclonal antibody used for childhood allergies as it interrupts the IgE-dependent allergic inflammatory cascade by binding to free IgE and preventing its binding to IgE receptors [13]. Etokimab is a human monoclonal IgG1 antibody that neutralizes IL-33 inflammatory responses. Preliminary clinical studies on biologics have demonstrated their efficacy on AD and asthma [14]. Additionally, several I/II clinical trials have revealed afezakinumab, nemolizumab, tezepelumab, secukinumab, GBR 830, and recombinant interferon-γ as emerging treatment options for AD as well other atopic comorbidities in the future [15]. This meta-analysis will systematically evaluate the efficacy and safety of biologics by including a randomized, placebo-controlled study of dupilumab in the treatment of children with AD, and provide an evidence-based reference for its clinical treatment. However, there is a lack of systematic reviews for pediatric AD. Our meta-analysis aims to provide data supporting the clinical application of biologics in treating pediatric atopic dermatitis.

Methods
This systematic review will follow the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. PROSPERO has accepted this protocol for review with the registration number CRD42022319052.

Ethics and dissemination
The study does not collect raw data and personal information and does not involve jeopardizing the rights of the participants. Ethical approval is not required. The results may be reported in publications and the media.

Eligibility criteria
Study design. All randomized controlled trials (RCTs) that evaluate the efficacy and safety of biologics for treating pediatric atopic dermatitis will be searched thoroughly. Study designs such as non-RCTs and animal studies will be excluded from the review.
Types of participants. Patients with atopic dermatitis aged 6 months to 18 years old, regardless of gender, the severity of their condition, and nationality.

Types of interventions.
Experimental patients will receive a biologic with or without other drugs, while the control patients will receive a placebo or non-biologic treatment.

Measurement of outcomes
Primary outcomes. The primary outcome is the percentage of patients who improved their EASI score from baseline by 75% or 90% or 100% (EASI 75/90/100) based on the decline rate in the Eczema Area and Severity Index (EASI) score.
Second outcomes. According to the evaluation standards, the Dermatology Life Quality Index (DLQI), the Numerical Rating Scale (NRS), the Investigator Global Assessment (IGA), body surface area (BSA), and incidence of adverse reactions are evaluated as secondary outcomes.

Electronic searches
Several databases like Embase, Cochrane Library, Web of Science, and PubMed will be searched from the inception of the study till 15th May 2022 to collect RCTs using biologics for treating pediatric atopic dermatitis. Besides, only English-language articles will be considered.

Search strategy
The searches will be carried out using a combination of subject headings and keywords. The keywords include "Atopic Dermatitis", "Atopic Neurodermatitis", "Upadacitinib", "Abrocitinib", "Lebrikizumab", "Dupilumab", "Tralokinumab" and "randomized controlled trial". Table 1 shows the search strategy in PubMed. The same search algorithm will be applied to all other databases.

Data collection and analysis
Study titles, abstracts, and full texts will be independently reviewed by two researchers (Rui Cao and Jiaxing Lu). We will also record the reasons for excluding irrelevant RCTs. Any disagreements will be settled by a third researcher (Zhao Chen). Fig 1 illustrates the study selection process.

Risk of bias assessment
Each trial will be evaluated independently by two researchers (Rui Cao and Jiaxing Lu) according to the Cochrane Risk of Bias Tool. We will assess random sequence generation, allocation concealment, blinding of intervention, blinding of outcome assessment, reporting of complete outcome data, selective reporting, and other biases.
There are three levels of study bias: high risk, low risk, and unclear risk.

Data synthesis and statistical analysis
We will conduct the meta-analysis using RevMan V.5.3.0 software. Continuous data are expressed as standardized mean difference (SMD) with 95% confidence intervals. Dichotomous data will be assessed using the risk ratio (RR) with 95% CIs. Assessment of heterogeneity. To determine statistical heterogeneity, we will calculate I 2 or use the chi-square test. It will be viewed as low or no heterogeneity if I 2 <50%, while I 2 �50% will be viewed as significant heterogeneity within the RCTs. If there is no statistical heterogeneity (I 2 <50% and P> 0.1), the fixed-effects model will be used for meta-analysis. If there is statistical heterogeneity (I 2 > 50% and P < 0.1), the random-effects model will be used for meta-analysis. Consequently, we will conduct a sensitivity or subgroup analysis to identify possible sources of heterogeneity.

Subgroup analysis.
In cases of insufficient studies, subgroup analysis will be conducted according to different types of biologics, the age range of participants, and the frequency as well as the course of the treatment.
Sensitivity analysis. Sensitivity analyses will be performed to check whether the results are robust and reliable, based on methodological quality, sample size, statistical models, and missing data.
Assessment of publication bias. The publication bias will be assessed with funnel plots if >10 studies are included in the meta-analysis. The asymmetry of the funnel plot will be checked by Egger's test.
Evidence quality evaluation. The quality of evidence will be categorized as high, moderate, low, or very low, based on their grades.

Discussion
The expected results may reveal that the efficacy of biological agents in the treatment of pediatric atopic dermatitis is more enhanced than hormonal therapy or immunosuppressants.

PLOS ONE
Additionally, these biological agents display good safety and have little impact on the teenage population.